The synthesis of novel nonclassical reversed bridge quinazoline antifolates as inhibitors of thymidylate synthase [1a,b]

Article abstract of DOI:10.1002/jhet.5570370512

2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one (3, AG337) a lipophilic thymidylate synthase inhibitor, is currently in clinical trials as an antitumor agent. On the basis of the crystal structure of 3 and the classical inhibitor 10-propargyl-5,8-dideazafolic acid (1, PDDF) with thymidylate synthase, we designed and synthesized a series of nonclassical 2-amino-6-substituted-3H-quinazolin-4-ones 4-13, with a variety of electron withdrawing groups in the side chain (with the exception of compound 4). Molecular modeling indicates that these reversed bridge (N9-C10) 6-substituted analogues orient their side chain C10-substituent such that it lies between that of 1 and 3. These compounds were obtained by reductive amination of 6-aminoquinazoline 16 and the appropriate aryl aldehyde 17 or aryl ketone 18. For analogues 11-13, the yield depended on the substitutents on the aryl ketone 18 (comparison of 11 and 13). With the exception of analogue 13, all the compounds in the series were poor inhibitors of thymidylate synthase from Lactobacillus casei, Pneumocystis carinii and human sources.